TET - Tet Methylcytosine Dioxygenase | Elisa - Clia - Antibody - Protein

Background

Tet Methylcytosine Dioxygenases (TET) are a family of enzymes that play a crucial role in DNA demethylation, an essential process for regulating gene expression and maintaining cellular identity. The TET family includes three members: TET1, TET2, and TET3, each encoded by separate genes. These enzymes catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and further oxidized derivatives, facilitating active DNA demethylation. This process is vital for various biological processes including development, differentiation, and cellular reprogramming. The discovery of TET enzymes has provided significant insights into epigenetic regulation and its implications in health and disease, particularly in cancer and developmental disorders.

Protein Structure

TET proteins share several conserved structural domains essential for their function:

• Catalytic Domain: Located at the C-terminus, this domain contains a double-stranded β-helix (DSBH) fold that coordinates the binding of Fe(II) and α-ketoglutarate, which are necessary cofactors for the oxidation reaction.
• Cysteine-rich and CXXC Domains: Present in TET1 and TET3, these domains are involved in DNA binding and recognition of methylated DNA.
• Regulatory Regions: These regions help in the proper localization of TET proteins within the nucleus and mediate interactions with other proteins involved in DNA repair and chromatin remodeling.

Classification and Subtypes

The TET family consists of three main enzymes:

• TET1: Highly expressed in embryonic stem cells and implicated in maintaining pluripotency.
• TET2: Frequently mutated in hematological malignancies and involved in hematopoietic stem cell differentiation.
• TET3: Predominantly expressed in oocytes, zygotes, and early embryos, playing a crucial role in reprogramming and early development.

Function and Biological Significance

TET enzymes are critical for several biological functions:

• DNA Demethylation: They convert 5mC to 5hmC and further oxidized forms, facilitating the removal of methyl groups from DNA and thereby reversing DNA methylation.
• Gene Regulation: By modulating the methylation status of gene promoters and enhancers, TET enzymes influence gene expression patterns crucial for development and differentiation.
• Cellular Reprogramming: TET-mediated DNA demethylation is vital for the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs).
• Stem Cell Maintenance: TET1 is particularly important in maintaining the pluripotency of embryonic stem cells.
• Development: TET3 is essential during early embryogenesis and for the epigenetic reprogramming that occurs after fertilization.

Clinical Issues

Mutations and dysregulation of TET enzymes are associated with several clinical conditions:

• Cancer: TET2 mutations are common in myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Altered TET function can lead to aberrant DNA methylation patterns, contributing to oncogenesis.
• Developmental Disorders: Mutations in TET genes can result in developmental abnormalities due to improper epigenetic regulation.
• Neurodegenerative Diseases: Abnormal TET activity and 5hmC levels have been implicated in neurodegenerative disorders such as Alzheimer's disease.

Summary

Tet Methylcytosine Dioxygenases (TET1, TET2, and TET3) are pivotal enzymes in the process of DNA demethylation, a key epigenetic modification that regulates gene expression. By oxidizing 5-methylcytosine to 5-hydroxymethylcytosine and further derivatives, TET enzymes facilitate active DNA demethylation, influencing various biological processes including development, differentiation, and cellular reprogramming. Dysregulation of TET enzymes is associated with numerous diseases, particularly cancers and developmental disorders, underscoring their importance in maintaining cellular and genomic integrity. Understanding the mechanisms and functions of TET enzymes continues to be a significant area of research with potential therapeutic implications.